Medicament dispensing device, medicament magazine therefor and method of removing a medicament from a medicament chamber

ABSTRACT

The invention relates to a medicament dispensing device, particularly a multi-dose powder inhaler, a medicament magazine thereof, and a method of removing a medicament from the medicament magazine as depicted in exemplary FIG.  1 . The inhaler has a mouthpiece ( 9 ) and an air channel ( 4 ) connected thereto, as well as a medicament magazine with at least one medicament chamber containing a powdered medicament. A drive current is produced in the air channel, while a vacuum flow ( 5 ′) can be produced by the drive current and a constriction formed in the air channel. This narrowest part of the air channel that produces the vacuum flow is connected to a removal opening ( 2 ) which communicates with a control opening ( 3 ), in order to form an emptying current through the control opening via the removal opening. In a preferred embodiment the at least one medicament chamber including the control opening, the removal opening and a fill opening are housing in the one-piece medicament magazine.

This application is the national phase entry under 35 U.S.C. § 371 ofInternational Application No. PCT/CH2007/000182, filed Apr. 13, 2007,which claims priority to European Application No. EP 06405160.0, filedApr. 13, 2006, each of which is hereby incorporated by reference in itsentirety.

The invention relates to the field of medicament dispensing devices witha multi-dose magazine, particularly multi-dose powder inhalers, andrelates to a medicament dispensing device according to the preamble ofthe independent claim. Also claimed is a medicament magazine for use inthe medicament dispensing device, and a method of removing a medicament,particularly a powdered medicament.

Inhalers are known from the prior art in which a connection is madedirectly to a medicament chamber by means of a vacuum flow produced byinhaling (Venturi) and a powdered medicament contained therein isremoved. In U.S. Pat. No. 6,655,381 a powdered medicament is placed inwells arranged in a circle in an annular magazine. A seal that closesoff the wells is removed substantially in its entirety and a Venturitube is arranged parallel to the magazine with the constriction abovethe well. Attached to the Venturi tube is a longer turbulence chamberwhich is needed as the medicament is essentially removed from the wellall in one go. With this device it is not possible to achieve accuratedosing of a medicament or adjustment to different dosages.

In addition, there are various inhalers in which a medicament chamber isopened by piercing. However, openings in a film made by piercing are notvery precisely defined, which means that on the one hand the preciseamount of a medicament removed is not known and also differences occurbetween successive removals. This is undesirable particularly withmedicaments the activity of which depends to a very high degree on thedosage.

In order to achieve the best possible turbulence in a medicament andthereby dissolve the carrier material and the active substance itself,in EP 1 475 115 and GB 2 340 758, a medicament chamber is essentiallydivided into an entry and exit chamber which are joined together by aconstricted passage. A medicament is placed only in the entry chamber.By piercing or introducing cannulas, an air flow is produced through themedicament chamber from the entry chamber through the constriction intothe exit chamber and out of the medicament chamber. In EP 1 475 115, forimproved emptying of the medicament chamber, the entry and exit caberare each provided with two openings. In both specifications, theopenings in the chambers are defined by the piercing.

In U.S. Pat. No. 5,715,810 a medicament chamber incorporated in anannular magazine is pierced on both sides. One piercing cannula isattached to a Venturi current, so as to produce an air flow through thechamber. The removal takes place in one step and cannot be metered, orcan only be metered poorly. Here, too, the chambers are defined bypiercing and pins used for this.

In WO 03/045483 a medicament chamber is pierced and a medicamentcontained therein is emptied out using an air flow produced by acompressed air source.

EP 0 547 429 discloses a cylindrical medicament magazine in which afresh medicament chamber is brought into registry with a removal openinginside the apparatus by a screwing movement. In the apparatus, the airflow is subdivided: while one part empties the medicament chamber, theother part is passed through the apparatus and is combined with themedicament air current as an encircling air current.

In WO 2005/002654 an air flow is injected through a medicament chamber.Individual medicament pouches are housed in an annular magazine. Duringuse the pouches are pushed out of the magazine from behind, therebysevering a sealing film and are coupled with a removal mechanism. At thesame time an air current is guided into and through the pouch at themaximum possible speed. To trigger aggregation of a powder and preventmedicament from being carried forward into successive inhalations, anindividual channel is provided downstream of each pouch. With anadditional bypass channel that circumvents the pouch and also opens intoa mouthpiece, the total volume of air inhaled is increased andinhalation facilitates or guarantees a sufficient air current beingpresent to transport the medicament to the user. Owing to the fact thatsome of the air current is deflected through the bypass channel, the aircurrent through the pouch is reduced, so that the removal process isprolonged. The removal of the medicament can thus be spread over asomewhat longer period of time instead of all being removed at once.

The powder inhaler from WO 2005/002654 is relatively complicated inconstruction. A number of different parts are present, some of whichmove and have to be coordinated with one another. Moreover, the removalof the medicament is not triggered by an actual Venturi principle, butrather there is an intake current passing directly through themedicament pouches, and this can be weakened by a bypass flow.

The aim of the invention is therefore to provide a medicament dispensingdevice, a medicament magazine for use in such a medicament dispensingdevice and a method of removing a medicament form a medicament chamberin which the removal is based on the Venturi principle and the amounttaken out can be metered accurately and reproducibly.

This aim is achieved by the medicament dispensing device, the medicamentmagazine, and the method, as defined in the claims.

The invention is based on the principle known from U.S. Pat. No.6,655,381, for example, of applying a Venturi-like vacuum flow to amedicament chamber and sucking the medicament contained therein out ofthe chamber by the vacuum and transporting it with the flow towards amouthpiece. There, the medicament travels with the air current in thelungs of the user inhaling it.

In the device and method according to the invention, a drive current isnow produced in an air channel, which as a result of a constriction inthe air channel produces a vacuum flow in this region. The narrowestpart of the air channel causing the reduced pressure flow is connectedto a removal opening of a medicament chamber. The removal opening isconnected to a control opening, so that an emptying current is formedthrough the control opening via the removal opening and through themedicament chamber. The emptying current is not connected to the drivecurrent before entering the medicament chamber, but combines with thedrive current after leaving the removal opening, so that a medicamentcarried along with the emptying current is transported with the drivecurrent towards the mouthpiece.

The removal and control openings are preferably integrated directly in amedicament magazine. If the openings or the medicament magazine as awhole are produced by injection moulding from plastics, for example,these openings are very precisely defined, in a way which is notpossible when an opening is produced by piercing, for example. Byintegrating the removal and control openings in the medicament magazine,these two openings are pre-defined and are fixed both before and afteropening a medicament chamber.

The control and removal openings form a major part of a throttlearrangement by which it is possible to control the emptying current andhence to vary the quantity of medicament removed per unit of time. Otherelements of the throttle arrangement with different effects may be theinner configuration of the medicament chamber itself, and theconstruction of the air channel connected to the removal opening,particularly its diameter.

As a result, the removal can be deliberately controlled, is preciselydefined and above all reproducible. A throttle effect and hence anemptying current can be deliberately selected on the basis of theaccurately defined but variable elements such as the control opening,removal opening, inner configuration of the medicament chamber and canalso easily be changed to other dosages, quantities and types ofmedicaments.

The inhaler may also have at least one bypass opening to assist theinhalation process, e.g. for children or people with weakened lungs.This bypass opening serves to form a bypass flow which also leads to themouthpiece and is preferably arranged downstream of a removal opening inthe direction of the mouthpiece. However, it does not have any directinfluence on a defined correlation between the vacuum flow, the removalopening and control opening.

A medicament chamber is preferably constructed so that at least some ofthe emptying current flows away over the medicament contained in themedicament chamber. By a suitable inner configuration of the medicamentchamber it is also possible to influence the disaggregation anddispersion of a medicament. For example, additional turbulence can beintroduced into an emptying current by means of a turbulence element,which is preferably formed by at least one part of the wall of themedicament chamber itself. This can increase the throttling effect or,if necessary, reduce it.

In the medicament chamber an additional vacuum flow can be produced, forexample by means of a special configuration of a chamber wall or bymeans of a turbulence element. This is preferably arranged in a directline between the control and removal openings, such that a medicamentlocated on the floor of the medicament chamber is detached by thisadditional vacuum flow in the chamber. This can be achieved by, forexample, the medicament chamber itself forming a kind of Venturi tube inall or part of the region between the control and removal openings.

A medicament magazine typically has a fill opening in addition to acontrol and removal opening. This fill opening is preferably formedindependently of the other two openings in the magazine. This has theadvantage that the fill opening can be very large, to assist with thefilling operation. The fill opening is closed off, preferably sealedwith a foil, after the introduction of a powder. If the medicamentmagazine is constructed as an annular magazine with a plurality ofmedicament chambers arranged in a circle therein, the control andremoval openings of each chamber are spaced from one another, preferablyon one side of the magazine, while the fill opening is arranged on theopposite side of the magazine. Thus, the opening of the control andremoval openings is also independent of the removal of a sealing foil.Preferably a medicament magazine has a plurality of medicament chambersand single doses contained therein. The number is preferably in therange from 1 to 100 or up to 200 single doses, preferably in the rangefrom 1-60, for example between 7-180 or 14-150, e.g. 30-120, 45-100, 30,90, 60, 120. For inhalers the maximum number of single doses ispreferably 60, for reasons of convenience and therapy.

An inhaler with a medicament magazine of this kind is very versatile inuse. Besides the various possibilities of coordination and deliberateand very precise dosing possibilities, particularly theirreproducibility, there is also the option of using the inhaler with awide range of amounts and types of medicament. It is relatively simpleto use a different medicament magazine, e.g. with a medicament chamberwith a different, e.g. greater or smaller, capacity. If a removalopening is accurately defined by the medicament magazine itself, anadjacent (vacuum) opening in the Venturi suction tube may also be madelarger without affecting the removal opening and hence the emptyingcurrent. As a result an inhaler can also be used with differentmedicament magazines, e.g. those with differently designed removalopenings. Owing to the fact that only one removal opening has to becoupled at the inhaler end, the remainder of the construction of theinhaler and also the medicament chamber, in relation to a removalmechanism, is substantially independent of the medicament magazine andvice versa. In particular, a medicament chamber may be very elongated,may have an angle, etc., and a control opening may be arrangedaccordingly at different locations in the magazine. This is possible asthe control opening is not directly connected to the arrangement of theVenturi tube, and in particular, the drive current produced in theVenturi tube and the emptying current formed by the coupling of thevacuum flow to the magazine have a different origin.

In the inhaler according to the invention essentially any kind ofopening mechanism is possible: a medicament chamber can be opened beforethe removal of the medicament by piercing, scraping or peeling off asealing foil that closes off the medicament chamber. A medicamentchamber is designed accordingly, preferably such that the removal andcontrol opening, which may also be referred to as control openings, arenot affected by the opening mechanism. In particular, they are notaffected by openings in the sealing foil itself or by an openingmechanism of the apparatus which produces such openings. This may beachieved for example by removing a sealing foil entirely from thecontrol openings before the medicament is taken out, or by making anopening in a sealing foil so big that its effect on the control openingsis negligible.

In one embodiment of the magazine, a medicament is emptied into apreliminary chamber, the preliminary chamber having a correspondingcontrol and removal opening which is connected to a vacuum flow forremoving the medicament. For this purpose, a medicament may be sealed inits own medicament chamber with a sealing foil which is preferablyopening by an opening means that may be installed in the chamber itself.In this embodiment this fill opening is arranged substantially on thesame side as the control openings. The preliminary chamber may be anintegral part of the medicament chamber or the medicament magazine, orit may be an integral part formed on an air channel. The advantage ofthe first variant is that a new unused chamber is available each timemedicament is taken.

In a preferred embodiment of the inhaler, two medicament chambers arejoined together through a common mouthpiece. In this way, the number ofsingle doses of medicament can be doubled. For this, the individualmedicament chambers of the two magazines are preferably arranged offsetfrom one another. However, it is also possible, when removing themedicament, to open one chamber of each magazine and take one medicamentfrom each. This is particularly advantageous if two medicaments have tobe taken which cannot be stored together, or if every second time adouble quantity of a medicament or medicament mixture has to be taken.For producing a medicament magazine and optionally also certain parts ofa device, pharmaceutically permitted materials are preferably used. Thefilms used may be multi-layer films, for example, which are suitable asfilms for peeling or piercing or for scraping off. Multi-layer filmsusually have a layer of PE, PP or PVC and an aluminium layer.Dependingon the particular requirement, a film is made more stable ortear-resistant, and this is pref done by incorporating a PET layer. Inpreferred material combinations, an outer layer of a film comprises thesame material as an injected-moulded magazine, for example. In this wayit is possible to seal or weld the different elements of a medicamentmagazine with the same materials. It is also possible to use sealinglacquer, e.g. heat-sealing lacquer. As a result, there are more possiblematerial combinations for the individual elements. A sealing lacquer isapplied, for example, to a film and/or to a magazine that is to beclosed off. It is also possible for a foil to have a layer of sealinglacquer directly. The strength of the seal is preferably also optimallytailored to the use, so that, for example, a peelable film adheresdirectly but removably to an elements which is to be sealed.

The compounds specified below may be used in the apparatus according tothe invention on their own or in combination. In the compounds specifiedbelow, W is a pharmacologically active substance and (for example) isselected from among the betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors. Moreover,double or triple combinations of W may be combined and used in theapparatus accin. Combinations of W might be, for example:

-   -   W denotes a betamimetic, combined with an anticholinergic,        corticosteroid, PDE4-inhibitor, EGFR-inhibitor or        LTD4-antagonist,    -   W denotes an anticholinergic, combined with a betamimetic,        corticosteroid, PDE4-inhibitor, EGFR-inhibitor or        LTD4-antagonist,    -   W denotes a corticosteroid, combined with a PDE4-inhibitor,        EGFR-inhibitor or LTD4-antagonist    -   W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or        LTD4-antagonist    -   W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.

The compounds used as betamimetics are preferably compounds selectedfrom among albuterol, arformoterol, bambuterol, bitolterol, broxaterol,carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol,terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81,KUL-1248 and

-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide-   5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one-   4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone-   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol-   5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol-   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(ethyl    4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic    acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1    dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric    acid-   8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol-   2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-benzaldehyde-   N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide-   8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one-   8-hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one-   5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one-   [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea-   4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol-   [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulphonamide-   3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzylsulphonamide-   4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol-   N-adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide,    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the acid addition salts of the    betamimetics are preferably selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, preferably the bromide salt, oxitropium salts,preferably the bromide salt, flutropium salts, preferably the bromidesalt, ipratropium salts, preferably the bromide salt, glycopyrroniumsalts, preferably the bromide salt, trospium salts, preferably thechloride salt, tolterodine. In the above-mentioned salts the cations arethe pharmacologically active constituents. As anions the above-mentionedsalts may preferably contain the chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts thechlorides, bromides, iodides and methanesulphonates are particularlypreferred.

Other preferred anticholinergics are selected from among the salts offormula AC-1

wherein X⁻ denotes an anion with a single negative charge, preferably ananion selected from among the fluoride, chloride, bromide, iodide,sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate,citrate, fumarate, tartrate, oxalate, succinate, benzoate andp-toluenesulphonate, preferably an anion with a single negative charge,particularly preferably an anion selected from among the fluoride,chloride, bromide, methanesulphonate and p-toluenesulphonate,particularly preferably bromide, optionally in the form of theracemates, enantiomers or hydrates thereof. Of particular importance arethose pharmaceutical combinations which contain the enantiomers offormula AC-1-ene

wherein X⁻ may have the above-mentioned meanings. Other preferredanticholinergics are selected from the salts of formula AC-2

wherein R denotes either methyl or ethyl and wherein X⁻ may have theabove-mentioned meanings. In an alternative embodiment the compound offormula AC-2 may also be present in the form of the free base AC-2-base.

Other specified compounds are:

-   tropenol 2,2-diphenylpropionate methobromide,-   scopine 2,2-diphenylpropionate methobromide,-   scopine 2-fluoro-2,2-diphenylacetate methobromide,-   tropenol 2-fluoro-2,2-diphenylacetate methobromide;-   tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide,-   scopine 3,3′,4,4′-tetrafluorobenzilate methobromide,-   tropenol 4,4′-difluorobenzilate methobromide,-   scopine 4,4′-difluorobenzilate methobromide,-   tropenol 3,3′-difluorobenzilate methobromide,-   scopine 3,3′-difluorobenzilate methobromide;-   tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;-   tropenol 9-fluoro-fluorene-9-carboxylate methobromide;-   scopine 9-hydroxy-fluorene-9-carboxylate methobromide;-   scopine 9-fluoro-fluorene-9-carboxylate methobromide;-   tropenol 9-methyl-fluorene-9-carboxylate methobromide;-   scopine 9-methyl-fluorene-9-carboxylate methobromide;-   cyclopropyltropine benzilate methobromide;-   cyclopropyltropine 2,2-diphenylpropionate methobromide;-   cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;-   cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;-   cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;-   cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;-   cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide.-   tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;-   scopine 9-hydroxy-xanthene-9-carboxylate methobromide;-   tropenol 9-methyl-xanthene-9-carboxylate-methobromide;-   scopine 9-methyl-xanthene-9-carboxylate-methobromide;-   tropenol 9-ethyl-xanthene-9-carboxylate methobromide;-   tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;-   scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide,

The above-mentioned compounds may also be used as salts within the scopeof the present invention, wherein instead of the methobromide the saltsmetho-X are used, wherein X may have the meanings given hereinbefore forX⁻.

As corticosteroids it is preferable to use compounds selected from amongbeclomethasone, betamethasone, budesonide, butixocort, ciclesonide,deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone,loteprednol, mometasone, prednisolone, prednisone, rofleponide,triamcinolone, RPR-106541, NS-126, ST-26 and

-   (S)-fluoromethyl    6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate-   (S)-(2-oxo-tetrahydro-furan-3    S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,-   cyanomethyl    6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylate    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the salts and    derivatives thereof, the solvates and/or hydrates thereof. Any    reference to steroids includes a reference to any salts or    derivatives, hydrates or solvates thereof which may exist. Examples    of possible salts and derivatives of the steroids may be: alkali    metal salts, such as for example sodium or potassium salts,    sulphobenzoates, phosphates, isonicotinates, acetates,    dichloroacetates, propionates, dihydrogen phosphates, palmitates,    pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418,Bay-198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585,V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

-   N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide-   (−)p-[(4aR*,    10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N²-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone-   cis    [4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic    acid]-   2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one-   cis    [4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]-   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts thereof, the    solvates and/or hydrates thereof. According to the invention the    acid addition salts of the PDE4 inhibitors are preferably selected    from among the hydrochloride, hydrobromide, hydriodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

The LTD4-antagonists used are preferably compounds selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001,MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

-   1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic    acid,-   1-(((1(R)-3    (3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic    acid-   [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic    acid    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts, solvates and/or    hydrates thereof. According to the invention these acid addition    salts are preferably selected from among the hydrochloride,    hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,    ydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By    salts or derivatives which the LTD4-antagonists may optionally be    capable of forming are meant, for example: alkali metal salts, such    as for example sodium or potassium salts, alkaline earth metal    salts, sulphobenzoates, phosphates, isonicotinates, acetates,    propionates, dihydrogen phosphates, palmitates, pivalates or    furoates.

EGFR-inhibitors which may be used are preferably compounds selected fromamong cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}    amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}    amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}    amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}    amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}    amino)-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl-carbonyl)amino]-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline-   4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}    amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo    [2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention these acid addition salts are preferably    selected from among the hydrochloride, hydrobromide, hydriodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

The dopamine agonists used are preferably compounds selected from amongbromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride,pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid andviozan, optionally in the form of the racemates, enantiomers,diastereomers thereof and optionally in the form of thepharmacologically acceptable acid addition salts, solvates or hydratesthereof. According to the invention these acid addition salts arepreferably selected from among the hydrochloride, hydrobromide,hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate.

H1-Antihistamines which may be used are preferably compounds selectedfrom among epinastine, cetirizine, azelastine, fexofenadine,levocabastine, loratadine, mizolastine, ketotifen, emedastine,dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine,doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine,promethazine, ebastine, desloratidine and meclozine, optionally in theform of the racemates, enantiomers, diastereomers thereof and optionallyin the form of the pharmacologically acceptable acid addition salts,solvates or hydrates thereof. According to the invention these acidaddition salts are preferably selected from among the hydrochloride,hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,hydrobenzoate and hydro-p-toluenesulphonate.

In addition, inhalable macromolecules may be used as disclosed in EP 1003 478.

In addition, the compound may from the group of the derivatives of ergotalkaloids, triptanes, CGRP-inhibitors, phosphodiesterase-V inhibitors,optionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

Examples of ergot alkaloid derivatives are: dihydroergotamine,ergotamine.

Examples of substances suitable for inhalation include medicaments,medicament formulations and mixtures containing the above-mentionedactive substances, and the salts and esters thereof and combinations ofthese active substances, salts and esters.

The invention is hereinafter described in more detail by means ofexamples. In the drawings:

FIG. 1 shows a detail of a powder inhaler with the removal principle,

FIG. 2 shows the removal principle, in simplified view,

FIG. 3 shows a medicament magazine as an annular disc,

FIG. 4 shows the medicament magazine with the medicament chamber open,

FIG. 5 shows the entire medicament magazine,

FIG. 6 shows a scale representation of the medicament magazine accordingto FIG. 3-5,

FIG. 7 shows a medicament chamber for different opening mechanisms,

FIG. 8 shows a double annular magazine with a combined air channel,

FIG. 9 shows a double annular magazine with separate air channels,

FIG. 10 shows a blister with internal structure and preliminary chamberas a medicament magazine,

FIG. 11 shows two embodiments of a blister with internal structure.

FIG. 1 and FIG. 2 show the removal principle for a powder 6 containing amedicament and contained in a medicament chamber, such as may be used ina powder inhaler. The medicament chamber is in the form of a cavity 7 ina plastics part preferably produced by injection moulding orthermoforming. The medicament chamber has, on an upper side, a removalopening 2 which is connected directly to an air channel 4. The airchannel is constructed as a Venturi tube. When the inhaler is used,sucking on a mouthpiece 9 produces a drive current 5 in the air channeland a vacuum current in the region of the constriction of the airchannel (Venturi effect). The powder in the cavity is sucked out intothe air channel 4 through the removal opening and together with thedrive current 5 is carried towards the mouthpiece and the person usingthe inhaler. As a result of the Venturi effect the maximum pressuredifference and the maximum velocity in the air current are found at theremoval opening. This guarantees efficient detachment of a medicamentfrom its support (dispersion of the powder). The medicament chamber alsohas on its upper side, the same side as the removal opening, a controlopening 3 through which air flows into and through the cavity and formsan emptying current. Some of this emptying current flows away over thepowder 6 and can produce an additional Venturi effect with a turbulenceelement 15 located in the cavity between the turbulence element and thepowder or the base of the cavity. The turbulence element may also havestructures, e.g. projections pointing into the medicament chamber, whichintensify the turbulence of the air and powder.

Every one of these measures and effects increases the formation ofturbulence in the cavity and hence the dispersion. Any clumps in thepowder can also be broken up in this way. The shape of the removalopening and the combining of the vacuum and emptying currents alsoinfluence the dispersion of the powder.

The medicament chamber comprises a fill opening 13 on the bottom,opposite the top. The fill opening 13 extends substantially over theentire lower surface of the cavity and is closed off with a sealing film12 once the powder has been placed in the cavity.

With this removal concept the removal of the medicament can be adaptedvery sensitively and in versatile manner to all kinds of medicaments,dosages and user requirements. This can be done by varying and adaptingthe emptying flow, which is affected by several parameters: the diameterof the air channel above the removal opening, the dimensions of theremoval opening, the configuration of the cavity, and the dimensions ofthe control opening. The special configuration of the medicamentmagazine also allows easy adaptation to different amounts, compositionsor consistencies of medicaments, e.g. by enlarging the cavity and/orchanging the opening diameter. The separate fill opening also allowsthis to be made as large as possible, so that a powder can be poured invery quickly and without having to be tailored to a special (small) fillopening. Also, because of the direct connection of a removal opening tothe air channel and the vacuum flow prevailing therein, no powder islost along lengthy passages or ducts.

If required, the air channel 4 has additional sidestream or bypassopenings which terminate in the air channel and are arranged offsetdownstream of a removal opening, towards the mouthpiece 9. This reducesthe suction force needed or creates crosscurrents in the air channel toassist with the dispersion of a powder contained therein.

FIG. 5 shows a multi-dose medicament magazine constructed as an annularmagazine 1, of the kind that may be used in a disc-type inhaler, forexample. In the annular magazine 1 the upper sealing film has beenremoved from five medicament chambers. The plan view shows one removaland one control opening for each medicament chamber. An annular magazineof this kind may be made in one piece by injection moulding, forexample. The upper sealing film is applied first. After filling, thecavity is closed off by means of the lower sealing film. Examples ofpreferred injection-moulding materials are PE, PP and PVC.

FIGS. 3 and 4 each show a diagonal view of a medicament chamber, showncut away. FIG. 3 shows a filled medicament chamber in which there ispowder 6 in the cavity 7. The removal and control openings are coveredby the upper sealing film 14 and are closed off thereby in airtight andwatertight manner. The lower fill opening, one of which is preferablyprovided for each cavity, is closed off by a lower sealing film 12. FIG.4 shows the same diagonal view of a medicament chamber after use. Theupper sealing film 14 has been removed. The air flow 5 over the removalopening is guided through a constriction in the channel (cf. FIGS. 1 and2), thereby producing a vacuum above this opening. The dimensions of theremoval and control opening are preferably such that the cavity isemptied as continuously as possible.

FIG. 6 shows a cross-section through a cavity, and a plan view of anannular magazine, drawn to scale, such as might be produced for a powdervolume of about 10 mm³ and 30 cavities, i.e. single doses, in an annularmagazine.

The quantity of fill volume of a single dose may be varied relativelyeasily by changing the depth and/or length of the cavity. As only theremoval opening can be connected to a vacuum flow, the control openingcan be arranged virtually anywhere in the magazine. It must not beadjacent to the removal opening on the same side of the annular magazinebut it could, for example, be arranged on an inner diameter of themagazine.

FIG. 7 diagrammatically shows a section through the structure of amedicament chamber, as it might be designed in order to be opened bydifferent opening mechanisms, such as peeling, scraping off or piercing,without affecting the control openings, i.e. the control and removalopening. FIG. 7 shows a cavity 7 with the removal and control opening 2,3 spaced apart from each other. The openings are set into a recess. Theheight V and width B of the recess can be adapted to the particularopening mechanism. If the openings are exposed by peeling off a sealingfilm applied earlier, the height V of the recess is preferably zero andthe width B (or area) of the recess corresponds to the width of thechamber. In known piercing processes, a sealing film would be piercedand the size and shape of a removal opening and a control opening wouldbe determined by the piercing tools. These are generally inexact and athrottled flow would not be defined and in particular would not bereproducible. In order to be able to use piercing as the openingmechanism and thereby make use of the precisely defined openings thatcan be made when the product is manufactured by the injection mouldingtechnique, the recess depth V>0 and the width B is chosen to be greaterthan the chamber width. As a result, piercing takes place independentlyof the actual removal and control opening. The piercing tool is selectedsuch that the foil is pierced over one or more areas which are greaterthan the area of the removal and control opening, such that anyinfluence of the pierced opening(s) is negligibly small in relation tothe control openings.

FIGS. 8 and 9 each show a section through a double medicament magazine,e.g. an annular magazine. The magazine substantially corresponds to twoannular magazines according to FIG. 3 which are arranged with theirreverse sides, i.e. the sides containing the fill openings 13, touchingin mirror image and are attached to one another or only pressedtogether. The two parts of the magazine are pushed together such thatthe individual medicament chambers 7 are not precisely opposite oneanother (the offset chamber is shown by dotted lines). In this way, amulti-dose inhaler of for example 30 doses can be converted into apreferred 60-dose inhaler. In FIG. 8 two air channels 4, 4′, whichbelong to an upper and lower part of the magazine, open into the samemouthpiece 89. The mouthpiece and air channels are made in one piece.Because of the offset arrangement of the medicament chambers 7 (shown bydotted lines in FIG. 7) powder can only be taken from one chamber, evenwhen the chambers are open. The air channel 4′ which is not in use canbe used for an additional air supply (bypass). However, it is alsopossible to arrange the chambers so that they are not offset from oneanother, so that two different medicaments, for example, can be takenfrom two chambers. FIG. 9 shows a mouthpiece 99 which subdivides the twoair channels 4,4′ so that no air can pass through a non-selected channelinto the mouthpiece 99. The mouthpiece may be rotated for example froman upper part to a lower part of the magazine.

FIG. 10 shows another embodiment of the invention by reference to amedicament magazine which is constructed as a foil blister with aninternal structure 101. This internal structure 106 has opening means,for example, in the form of piercing points or cutting edges by means ofwhich a sealing foil that closes off a medicament chamber is opened bypressing the internal structure outwards. The internal structure ispreferably also constructed so that it gives a degree of stability tothe medicament chamber. In this way, a powder contained therein isprotected from mechanical influences from the outside or, in particular,when the chamber is opened. This is important for powdered medicamentcarriers for inhalers, as the inhaling or dosing of a compacted powderis no longer possible, or is no longer possible in a defined manner.

The foil blister 101 has, in the region of the actual medicamentchamber, a preliminary chamber 105. The preliminary chamber 105 has aremoval opening 2 and a control opening 3. The delivery of the powder 6from the blister is preferably effected as follows: the contents of theblister are emptied or introduced into the preliminary chamber 105 withthe aid of the internal structure, preferably directly during the actionof loading an inhaler. The preliminary chamber has a removal opening 2which may be in the form of a through-bore and is connected to a Venturisuction tube 104. As a result of the Venturi effect, the maximumpressure difference is present at the through-bore, enabling the powderto be drawn out of the preliminary chamber 105 in metered amounts. Atthis point the air current 5 reaches its maximum speed, thus allowingefficient detachment (dispersion) of an active substance from thecarrier.

Preferably a blister with an integrated preliminary chamber is produced,such that a medicament magazine with a fill opening, removal opening andcontrol opening in turn forms a unit, while the openings are matched toone another, depending on the application. One advantage of this variantis that a fresh preliminary chamber is provided for each inhalation.Another variant in which a fresh suction tube or part of a suction tubeis available for each removal is when the blister is formed with anintegrated preliminary chamber and suction tube. Any medicament residueson the walls of the suction tube, which in particular occur directly inthe region of the removal opening would thus not affect subsequentremovals. In another variant the preliminary chamber is in turn anintegral part of the suction tube, but is independent of the foilblister and the actual medicament chamber.

To illustrate blisters with an internal structure 101 FIG. 11 shows twoexamples on a larger scale. The Figure shows one medicament chamber inthe filled, unused state in each case. Powder 6 is at least partlyenclosed by the internal structure 3 and protected from externalmechanical effects, but particularly from being compressed as theinternal structure is pressed out of the medicament chamber. Theinternal structures have piercing points or cutting edges 109 with whicha sealing foil 107 is pierced or cut open and torn or cut away as thechambers are opened.

The internal structure may be connected to the blister, e.g. sealed onits reverse side with a film so as not to fall into the preliminarychamber depending on the position of the blister. However, if thepreliminary chamber is an integral part of the blister or eachindividual medicament chamber located therein, this measure may not benecessary. An internal structure of this kind may also serve as aturbulence element as well or in particular if it is freely positionedin the preliminary chamber. The internal structure may also provideadditional turbulence by means of an emptying current passing throughthe preliminary chamber and thus additionally contribute to thedisaggregation and dispersion of the powder. The internal structure ispreferably very open in design, so that an air current can penetrateinto and through the internal structure is possible from many sides.This contributes to emptying a medicament chamber as completely aspossible and additional air turbulence.

The internal structure, preliminary chamber and suction tube arepreferably formed by injection moulding a plastic. However, it is alsopossible to produce individual parts thereof by a thermoforming processor, in the case of internal structures, to stamp and form them from afoil, e.g. a metal foil.

1-24. (canceled)
 25. Medicament dispensing device comprising amouthpiece (9) and an air channel (4) connected therewith, as well as amedicament magazine with at least one medicament chamber containing amedicament, wherein a drive current comprising a vacuum flow can begenerated in the air channel, characterised in that a most narrow regionof the air channel that produces the vacuum flow, is connected to aremoval opening (2) provided by the medicament magazine, this removalopening being connected to a control opening (3), to form an emptyingcurrent through the control opening via the removal opening. 26.Medicament dispensing device according to claim 25, wherein the controland removal openings (3,2) are provided in the medicament magazine. 27.Medicament dispensing device according to claim 25, wherein a bypassopening (8) is provided in the air channel (4) for forming a bypassflow, the bypass opening being arranged downstream of the removalopening (2) in the direction of the mouthpiece (9).
 28. Medicamentdispensing device according to claim 25, having a throttle arrangementfor varying the amount of medicament removed per unit of time. 29.Medicament dispensing device according to claim 28, wherein the throttlearrangement comprises the control opening (3), the removal opening (2),the inner configuration of the medicament chamber and the configurationof the air channel connected to the removal opening.
 30. Medicamentdispensing device according to one of claim 25 for administering amedicament that contains an active substance or a combination of activesubstances selected from among the group of betamimetics,anticholinergics, steroids, antiallergics, ergot alkaloid derivatives,triptanes, CGRP antagonists, the phosphodiesterase-V inhibitors,phosphodiesterase-IV inhibitors, LTD4-antagonists, EGFR-kinaseinhibitors.
 31. Medicament magazine (1) comprising a plurality ofmedicament chambers, each having at least one opening for the removal(2) of a medicament, characterised in that the medicament chamber has afill opening (13) and the removal opening (2) is connected to a controlopening (3), wherein the removal opening (2) can be attached to a vacuumflow in order to form an emptying current through the control opening(3) via the removal opening (2), and wherein the removal opening, thecontrol opening and the fill opening are spaced from one another. 32.Medicament magazine according to claim 31, wherein the removal opening(2) and control opening (3) are integrated and predefined in themedicament magazine.
 33. Medicament magazine (1) comprising a pluralityof medicament chambers having at least one opening for the removal (2)of a medicament, characterised in that the medicament chamber has a fillopening (13) and the removal opening (2) is connected to a controlopening (3), the removal opening (2) being connectable to a vacuum flowin order to produce an emptying current through the control opening (3)via the removal opening (2) and wherein the removal opening (2) andcontrol opening (3) are integrated and predefined in the medicamentmagazine.
 34. Medicament magazine according to claim 33, wherein thefill opening (13), removal opening (2) and control opening (3) arearranged at a spacing from one another.
 35. Medicament magazineaccording to claim 31, wherein the magazine is annular and a pluralityof medicament chambers are arranged in a ring in the magazine. 36.Medicament magazine according to claim 31, wherein the fill opening (13)is arranged in a side of the magazine opposite the removal and controlopening (2,3).
 37. Medicament magazine according to claim 31, whereinthe fill opening (13) is arranged on the same side of the magazine asthe removal and control opening (2,3).
 38. Medicament magazine accordingto claim 31, wherein a turbulence element (7) is arranged in themedicament chamber.
 39. Medicament magazine according to claim 38,wherein the turbulence element (7) is formed by at least a part of thewall of the medicament chamber.
 40. Medicament magazine according toclaim 31, produced in one piece by injection moulding.
 41. Multi-dosepowder inhaler comprising a medicament magazine according to claim 31.42. Multi-dose powder inhaler according to claim 41, comprising 60medicament chambers with single doses of medicament.
 43. Method ofremoving a medicament from a medicament chamber, wherein a medicament isremoved from the medicament chamber by the formation of a vacuum flow,and wherein the vacuum flow produces an emptying current through themedicament chamber, characterised in that the vacuum flow is part of adrive current (5) and is connected to a removal opening (2), defined bythe medicament magazine, which removal opening is connected to themedicament chamber, wherein the emptying current is not connected withthe drive current before entering the medicament chamber.
 44. Methodaccording to claim 43, wherein the quantity of medicament to be removedper unit of time is determined by the strength of the emptying current,while the latter can be varied by means of a throttle arrangement. 45.Method according to claim 43, wherein at least some of the emptyingcurrent flows away over the medicament contained in the medicamentchamber.
 46. Method according to claim 43, wherein an additional vacuumflow in the medicament chamber is produced by means of an innerconfiguration of the medicament chamber.
 47. Method according to claim43, wherein a medicament is emptied into a preliminary chamber (105)which is attached to a vacuum flow via a removal opening (2) for theremoval of the medicament.
 48. Method according to claim 43, wherein amedicament chamber is opened before the removal of medicament, bypiercing, scraping off or peeling a sealing foil (14) that closes offthe medicament chamber.